Every year, 300,000 newborns are treated for infection in the United States, at a cost of over $800 million. While the prevalence of severe bacterial infection in neonates is low (from 1 to 10 per-1000 live births), mortality is high (20-75%) and has not decreased despite the development of potent antibiotics over the last decade. In particular, blood stream infections (sepsis) develop very rapidly, and are often fatal within hours of neonatal exposure to pathogens. Consequently, treatment is often initiated empirically because of nonspecific clinical signs or maternal risk factors, and an average of 17 infants are treated for each one who is truly infected. For general information on neonatal infection including sepsis see for example references [1-6].
Multiple immunologic impairments in neonates, such as low levels of IgA, IgM, and some IgG subclasses, a smaller neutrophil reserve pool than that of adults (10% of adult levels at birth), and functional deficiencies in circulating neutrophils put neonates at risk for serious infection upon exposure to pathogens. Clinical practice thus defines a series of risk factors whose presence dictates clinical decisions aimed at prevention or anticipatory treatment of neonatal infection. See references [7-13] for information on neonatal immune system deficiencies, and references [14-15] for information on neonatal infection risk factors and their relationship to clinical decisions.
Three major preventative and treatment pathways are commonly followed: 1) mothers at risk for vertically transmitting infection (e.g. mothers with known colonization with Group B Streptococcus, premature rupture of membranes, maternal fever, spontaneous onset of labor before term) may be treated perinatally with antibiotics; 2) infants with a single maternal risk factor or who are mildly premature may be monitored for 24 hours in an intermediate or intensive care nursery; and 3) infants with multiple risk factors and/or clinical signs of infection may undergo a complete diagnostic evaluation, including blood and CSF cultures, CBC, and chest X-rays. Treatment with broad spectrum antibiotics is usually initiated, and infants remain in the hospital until infection can be ruled out. For information on neonatal infection treatment using antibiotics see references [4-6, 16].
Currently, some clinicians use serum C-reactive protein (CRP) to exclude the diagnosis of infection in at-risk neonates. CRP is secreted by hepatocytes as a component of the acute-phase response, and increases in serum close to 1,000-fold in response to tissue insult. Serum CRP elevation depends upon the production of IL-6 and TNF-.alpha. and their transport to the liver, where CRP is then synthesized. In the absence of clinical signs of infection, three negative CRP measurements on consecutive days provide convincing evidence that an infant is not infected. One positive CRP measurement suggests that infection is a possibility. For information on the use of CRP for diagnosis of neonatal infection see references [17-18].
Serum CRP assays have several disadvantages. The time delay between bacterial exposure and elevated serum CRP may range from hours to days. Consequently, while CRP may help to retrospectively exclude infection and to support discontinuation of antimicrobial therapy, CRP is not commonly used for identifying infants for whom antibiotic treatment may be safely omitted. Moreover, CRP levels in serum may be increased nonspecifically, as is seen in trauma and other forms of physiological stress (see references [19-20]). The use of CRP as an infection indicator may thus lead to unnecessary treatment of uninfected neonates. In addition, serum CRP elevation indicates only bacterial infection, and not viral infection.
Bacterial cultures are also commonly used for diagnosing neonatal infection. Results from bacterial cultures are generally not available for 24-48 hours, after treatment decisionsare commonly made. Thus, bacterial cultures are not used to rule out infection at initial evaluation. Also, bacterial cultures may have high false negative rates at early time points. For information on the use of bacterial cultures for neonatal infection diagnosis see reference [57].
Current well-established diagnostic tests for neonatal infection, including CRP and blood cultures, are confirmatory in nature and are not generally used for making treatment decisions at initial evaluation. Since neonatal sepsis is often fulminant and fatal within hours of exposure to antigen, CRP and bacterial culture tests do not usually eliminate the need to treat and confine at-risk neonates before test results are available.
An article by Davis et al. [69], herein incorporated by reference, describes a quantitative flow cytometric assay for leukocyte high-affinity Fc receptor (CD64) expression, and proposes its use as a diagnostic indicator of systemic acute inflammatory response. The receptor CD64 is not seen to be increased until six hours after exposure to interferon-.gamma. or G-CSF, however. Presumably, the elevation of CD64 is dependent on several levels of protein synthesis, and CD64 levels measured at early time points reflect not only antigen presence but also a particular stage of protein synthesis. In addition, the assay described by Davis et al. requires the use of as much as 100 ml of blood, much more than can be acceptably sampled from a neonate.
Davis et al. also report evaluating a number of potential infection indicators, including leukocyte CD11a, CD11b, CD16, CD18, CD23, CD32, and HLA-DR, and finding no correlation between the expression of the potential indicators and the presence of infection or other laboratory tests.
Gendrel et al. [67] propose a serum pro-calcitonin assay for neonatal infection diagnosis. Pro-calcitonin has not yet proven reliable enough for use as an indicator of neonatal infection, however. While pro-calcitonin is slightly elevated in infants with viral infection, bacterial colonization, or neonatal distress, it is only highly elevated in infants with bacterial sepsis.
Other potential indicators of neonatal infection have been proposed by many investigators, including IL-6, IL-2, hematological scoring systems, gastric aspirate studies, bacterial antigen tests, and more (see references [4, 5, 17, 58-66]).